Experience With Primary Liver Transplantation
Across ABO Blood Groups
R.D. Gordon, S. Iwatsuki, C.O. Esquivel, S. Todo, L. Makowka, A. Tzakis,
J.W. Marsh, and T.E. Starzl
T
HE LIVER has long been regarded as a
privileged organ which can be transplanted across incompatible ABO blood
groups with little risk of hyperacute rejection. l
However, in a recent review of 671 first,
second, and third liver transplants we found a
significant advantage for ABO donor-recipient identity for primary liver transplants. 2
Although a large number of ABO mismatched grafts were successful, graft survival
for primary liver grafts between ABO identical donor-recipient pairs was significantly better than grafts between ABO compatible but
nonidentical or ABO incompatible donorrecipient pairs.
The extent to which urgency of transplantation influenced these results was not fully
assessed. An urgent factor existed in many of
the transplants between ABO mismatched
donor-recipient pairs. We here report a review
of 745 primary liver transplants performed
between Jan I, 1981 and Dec 31, 1986 at the
University Health Center of Pittsburgh in
which the early outcome of primary liver
transplantation across ABO blood groups was
assessed in relationship to the urgency of
transplantation.
MATERIALS AND METHODS
Case Material
Seven hundred forty-five patients received primary
liver transplants at the University Health Center of
Pittsburgh between Jan I, 1981 and Dec 31, 1986. All
patients were followed through March I, 1987. Immunosuppression was cyclosporine and prednisone as described
elsewhere. 3 Since December 1983, Orthocloneo OKT3
monoclonal antibody (Ortho Pharmaceuticals, Raritan,
NJ) has been given for ten to 21 days for treatment of
acut.e cellular rejection of during periods of reduced
cyc1osporine coverage.
Recipient selection was based on medical need, estimated liver size and body weight. Preference was usually
given to ABO blood group identity except in cases of
medical urgency or donor scarcity, such as for small
children. HLA typing and lymphocytotoxic cross-matching were done retrospectively and were not used in
recipient selection.
ABO Blood Group Matching
The donor-recipient pairings according to ABO blood
group are summarized in Table I and Fig 1. There were
664 ABO identical pairings. ABO mismatched transplants were divided into two classes: (I) ABO compatible
but nonidentical grafts (0 to A, B, or AB; A or B to AB)
in which a graft-v-host (GVH) response may occur,
usually manifested by a self-limited hemolytic anemia 12
to 21 days after transplantation" and (2) ABO incoinpatible grafts (A to B; B to A; A, B, or AB to 0). There were
62 ABO compatible but nonidentical (GVH) pairings and
19 ABO incompatible pairings.
There were 333 male and 412 female recipients. There
was a higher porportion (55.6%) of males in the ABO
incompatible pairings than in the ABO identical (44.6%)
or GVH (42.9%) pairings, but recipient sex has no
influence on graft survival.
The patients ranged in age from 2 months to 76 years
(mean 26.9 ± 19.4, SD years) including 289 children
(less than 19 years of age) and 456 adults. The age
distribution of the patients according to ABO blood group
pairings is shown in Fig 2. A higher proportion of ABO
mismatched grafts involved small children for whom the
scarcity of organs is always severe.
Indications for Liver Transplantation
The indications for liver replacement are summarized
in Fig 3. Cirrhosis (mostly chronic aggressive hepatitis
From the Department of Surgery. University Health
Center of Pittsburgh, University of Pittsburgh; and the
Veterans Administration Medical Center. Pittsburgh.
This study was supported by Research Project Grant
No. AM-29961 from the National Institutes of Health.
Bethesda. Maryland.
Leonard Makowka is the recipient of a Centennial
Fellowship from the Medical Research Council of
Canada.
Address reprint request to Thomas E.Starzl. MD.
PhD. Falk Clinic. Department of Surgery. 3601 Fifth
Ave, Room 218. Pittsburgh. PA 15213.
© 1987 by Grune & Stratton. Inc.
0041-1345/87/1906/0043$3.00/0
TrBIJsplantation Proceedings. Vol XIX. No 6 (December), 1987: pp 4575-4579
4575
4576
GORDON ET AL
Table 1. Donor-Recipient ABO Matches
Group 0
Group A
316
21
18
3
3
282
2
2
9
57
16
4
Group 0
Group A
Group B
Group AB
Group B
NUMBER OF PATIENTS
Group AB
250 r-----------------------------,
226
3
200
9
but also including some cases of cryptogenic and Laennec's cirrhosis), primary biliary cirrhosis, sclerosing cholangitis, inborn errors of metabolism, and primary liver
tumors were the most common indications in adults.
Biliary atresia, inborn errors of metabolism, and cirrhosis
were the most common indications in children. The
majority of ABO mismatched transplants were performed for biliary atresia and cirrhosis, two of the most
common indications for transplantation in younger
patients.
150
100
50
o
Statistical Analysis
1 ST
Survival analysis was performed using BMDP IPC
(BMDP Statistical Software, Los Angeles, CAl on an
IBM/PC-AT microcomputer.
2ND
:lRD
4TH
5TH
6TH
7TH
8TH
DECADE
RESULTS
Fig 2. The age distribution of liver transplant recipients. Many of the ABO mismatched grafts were given
to younger patients. 1'!11. incompatible; l1li. GVH; •• ABO
identical.
Early survival for the 745 patients is shown
in Fig 4A and is 86.4% at 30 days at 72.4% at
180 days. Survival of patients under 4 years of
age, which includes 23.5% of the recipients of
ABO mismatched grafts was not different
than survival of older patients (Fig 4B).
Graft Survival
Four hundred twenty-two (56.6%) of the
745 grafts are functioning 3 months to more
than 5 years after transplantation. In 139
cases, patient death resulted in graft loss. The
remaining grafts were lost when retransplantation was performed for rejection (74 cases),
Patient Survival
CIRRHOSIS
BI LlARY ATRESIA
PRIMARY BILIARY CIRRHOSIS
INBORN ERRORS
SCLEROSING CHOLANGITIS _
GROUP 0
GROUP A
"'"'"' c"" ru""
GROUP B
GROUP AB
40
20
60
80
1007.
PERCENTAGE OF GRAFTS
•
IDENTICAL
ISlIll
GVH
I22J INCOMPATIBLE
ACUTE HEPATIC FAILURE
FAMILIAL CHOLESTASIS
SECONDARY BILIARY CIRRHOSIS
BUDD CHIARI SYNDROME
NEONATAL HEPATITIS
CONGENITAL FIBROSIS
212
149
114
IT '"
54
85
30
15
11
8
7
6
~
100
50
0
150
200
250
NUMBER OF PATIENTS
Fig 1. ABO donor-recipient compatibility classified
according to recipient ABO blood group. GVH (graftv-hostl refers to ABO compatible but not identical
graft-recipient pairs (such as 0 to A. B. or AB). Most of
the ABO mismatched grafts were given to recipients of
A. B. and AB blood types •• Identical; l1li. GVH; ~.
incompatible.
Fig 3. The major indications for liver transplantation according to ABO graft-recipient match. Most of
the ABO mismatched grafts were given to recipients
with chronic aggressive hepatitis (cirrhosis) or biliary
atresia. the two most common indications for transplantation ••• ABO identical; II. GVH; 1'!11. incompatible.
4571
ABO BLOOD GROUPS IN LIVER TRANSPLANTATION
:7. SURVIVAL
~ I
~
,
---L _____ :___ .__:
8
--,
~l
----L--
~
I
I
I
40 Fig 4. (A) Patient and primary graft survival for 745 liver
transplant recipients. (B) Survival for recipients under 4
years of age at the time of
transplantation was not significantly different than survival of
patients over 4 years of age.
20
I
i
L
I
I
~
I.~ . L._
o
I
L_-,-- ..1 .. _ .• _L_L_J.
60
technical complications (63 cases), primary
graft failure (44 cases), or graft infection (4
cases). 59.4% of the ABO identical grafts are
functioning, compared to 40.3% of the GYH
(ABO compatible but mismatched) grafts
and 42.1 % of the ABO incompatible grafts
(P <.04, Fig 5).
Early survival (out of 180 days) for the 745
grafts is shown in Fig 4A. Thirty-day survival
is 77.3% and 180-day survival is 63.7%. Early
graft survival based on ABO match is shown
in Fig 6A. Thirty-day graft survival is 79.0%,
67.2%, and 52.6% for ABO identical, GYH,
and ABO incompatible pairings, respectively,
and 66.0%, 46.5%, and 39.5% at 180 days,
respectively. There is a highly significant
ABO MATCH:
IDENTICAL
GVH
INCOMPATIBLE
p < 0.04
PERCENTAGE OF GRAFTS
Fig 5. The fate of 745 primary liver grafts according
to graft-recipient ABO match. Significantly more grafts
were lost in the ABO mismatched cases .•• functioning;
l1li. retransplanted; ~. died.
_J
r
l
L._.I.-
:J
4 YEARS OR UORE (614) .--.-UNDER 4 YEARS (131)
p
L_--,--.J _.L...J......-a......J_
I
120
180
120
60
o
DAYS AFTER TRANSPLANTATION
!
> 0.45
,L..I __ _
180
advantage in early graft survival for ABO
identical grafts when compared to the two
classes of ABO mismatched grafts
(P < .002).
The Factor of Clinical Urgency
Our last effort to develop a clinical index to
relate transplant outcome to pretransplant
clinical risk factors such as serum bilirubin,
prothrombin time, previous biliary or portosystemic shunt surgery, ascites, nutritional
status and encephalopathy showed a poor
correlation between outcome and risk factor
score for most patients. 5 For purposes of the
present study, we considered a transplant to
be urgent only for recipients with severe
encephalopathy (grade 3 or grade 4), active
gastrointestinal bleeding, or in intensive care
at the time of transplantation. Survival of
such urgent patients was significantly less
than survival for other patients (P < .01).
Each case of transplantation between ABO
mismatched donor and recipient pairs was
retrospectively reviewed to determine whether
or not the patient was transplanted in such
urgent circumstances. For the ABO identical
grafts, it was not feasible to individually
review all 664 cases. However, the patient
status at the time of transplantation is kept in
a computer registry and it was thus possible in
many of cases to determine whether or not a
4578
GORDON ET Al
" SURVIVAL
A
100" . , - - - - - - - - - - - - - - - - ,
BRESLOW p = 0.002
UANTEl-COX P = 0.002
c
B
r.------a-R-Es-l-o-w-P--~-0--.016
BRESLOW p = 0.04
UANTEl-COX P - 0.02
UANTEl-COX p - 0.037
,
l[-1...-:
80. :
60
I
j :----:
I·
L___.
H:"······L:::~~~::·:~~~i
I '··············,···..··_···"-··1 J
40
t:·:~1
l
IDENnCAl (662) _ _
GVH (64) ------
20
INCOUPAnBlE (19) ..........
o
I
I
,
~
I
I
l...L.....I.......J...L..L-'-'_~ r
30 60
90 120 150 180 21 0
I
I __
~.~
I
·····1
i
IOENnCAl (632) _
GVH (52) -----
l
':~~~:~L(:'~~J
30
60
90 120 150 180 21 0
IDENnCAl (611)
NOT IDENTICAL (67)·····
t'1-< LW-'_L...
30
I
.1~
60 90 120 150 180 210
DAYS AfTER TRANSPlANTATION
Fig 6. (AI Survival for 745 primary liver transplants based on donor-recipient ABO match. (BI Survival based on
donor-recipient ABO match for primary liver transplants in patients considered clinically stable at the time of
transplantation. Ie) Survival based on donor-recipient match for primary liver failure with graft loss to technical
failure excluded. ABO compatible but not identical IGVH) and ABO compatible donor-recipient combinations have
been pooled into a single class of "not identical."
patient was in intensive care just prior to
transplantation. There is a significantly
higher proportion of urgent patients in the
ABO mismatched graft-recipient classes
(P < ,01, Fig 7).
Figure 6B presents an analysis of the survival data when only patients considered stable at the time of transplantation are included.
Even with the urgent cases removed from
consideration for all the ABO mismatched
(and for at least some of the ABO identical)
grafts, early graft survival for ABO mismatched grafts is significantly less than survival for ABO identical grafts (P < .05).
of this graft had nothing to do with the ABO
mismatch.
Figure 6C shows graft survival with technical graft losses removed from the analysis.
The difference in survival between ABO identical and ABO mismatched grafts is not statistically significant (Breslow, P = .11 and Mantel-Cox, P = .07). However, if both classes of
ABO mismatched grafts are combined, the
difference in survival between ABO identical
ABO MATCH:
IDENTICAL
Technical Graft Losses
Another possible source of bias in the data
is graft loss from technical complications
including hepatic artery or portal vein thrombosis or major biliary tract complications. For
example, one ABO incompatible graft was
lost when a patient with an anomalous
superior vena cava developed fatal cerebral
edema while on veno-venous bypass during
the anhepatic phase of surgery. Obviously loss
GVH
INCOMPATIBLE
p < 0.01
PERCENTAGE OF GRAFTS
Fig 7. Donor-recipient ABO matches classified
according to the clinical urgency at the time of transplantation. This is a significantly higher proportion of
urgent cases in the ABO mismatched groups . •• stable;
III. urgent.
4579
ABO BLOOD GROUPS IN LIVER TRANSPLANTATION
and ABO nonidentical grafts, with technical
losses excluded, is significant (P < .05).
DISCUSSION
The presence of preformed antibody to
donor transplantation antigens such as ABO
blood group substances or to HLA antigens
remains the most prohibitive barrier in renal
transplantation. In liver transplantation, the
frequency with which successful transplantation can be accomplished in the presence of
preformed antibody to ABO blood group antigens or antidonor lymphocytotoxic antibodl
stands in striking contrast to the typical
course of events in renal transplantation.
The results of this study support our previous report that liver transplantation across
ABO blood groups is usually successful, but
not without risk. 2 Even when the data are
adjusted to remove very high risk patients,
there remains a statistically significant advantage in survival for ABO identical grafts. We,
therefore, continue to give preference to ABO
compatibility in the selection of liver transplant recipients, except in cases where medical urgency and donor scarcity justify taking
an extra risk.
Part of the disadvantage in graft survival
associated with ABO mismatched grafts may
lie in the added complexity of clinical managment that may result when graft-v-host disease (GVHD) is present. Inappropriate
changes in therapy, especially in immunosuppression, might complicate the course of
patients with ABO mismatched grafts.
In this retrospective analysis, data were not
available to assess the significance of preexisting recipient anti-A or anti-B isoagglutinating
antibody titers in the recipients of ABO
incompatible grafts. Further studies are
clearly warranted and are underway at this
and other liver transplant centers. Only a
deliberate prospective analysis of individual
cases will clarify the nature of the increased
risk of liver transplantation across ABO blood
groups.
REFERENCES
I. Starzl TE, Putnam CW, Ishikawa M, et al: Trans-
plant Proc 6:129, 1974
2. Gordon RD, Iwatsuki S, Esquivel CO, et al: Surgery
100:342, 1986
3. Starzl TE, Iwatsuki S, Shaw BW Jr, et al: Transplant Proc 17:250, 1985
4. Ramsey G, Nusbacher J, Starzl TE, et al: New Eng
J Med 311:1167,1984
5. Shaw BW Jr, Wood RP, Gordon RD, et al: Semin
Liver Dis 5:385, 1985
6. Gordon RD, Fung JJ, Markus B, et al: Surgery
100:705, 1986